A large lung gene expression study identifying IL1B as a novel player in airway inflammation in COPD airway epithelial cells
- 502 Downloads
Chronic obstructive pulmonary disease (COPD) is a chronic and progressive lung disease characterized by a mixture of small airway disease and lung tissue parenchymal destruction. Abnormal inflammatory responses to cigarette smoking and other noxious particles are generally thought to be responsible for causing of COPD. Since airway inflammation is a key factor in COPD progress, it is crucial to unravel its underlying molecular mechanisms. Unbiased analysis of genome-wide gene expression profiles in lung small airway epithelial cells provides a powerful tool to investigate this.
Gene expression data of GSE611906, GSE20257, GSE8545 were downloaded from GEO database. All 288 lung small airway samples in these cohorts, including donors with (n = 61) and without (n = 227) COPD, were chosen for differential gene expression analysis. The gene ontology (GO) function, Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses, gene co-expression network analysis (WGCNA) and protein–protein interaction (PPI) network analysis were performed. Subsequently, the analyses of IL1B expression level, the Pearson correlation between IL1B and several COPD biomarkers were performed using other cohorts to validate our main findings.
With a change ≥ twofold and P value < 0.05 cutoff, we found 38 genes were up-regulated and 114 genes were down-regulated in patients with COPD compared with health controls, while using cutoff fold change 1.5 and P value < 0.05, there were 318 genes up-regulated and 333 genes down-regulated. Among the most up-regulated genes were IL1B, CCL2, CCL23, and CXCL14, all implicated in inflammation triggering. GO, KEGG and WGCNA analysis all disclosed IL1B was highly correlated to COPD disease trait. The expression profile of IL1B was further validated using independent cohorts from COPD airway epithelium, lung tissue, sputum, and blood. We demonstrated higher IL1B gene expression in COPD small airway epithelial cells, but not in COPD lung tissue, sputum, and blood. Strong co-expression of IL1B with COPD biomarkers, such as DUOX2, MMP12, CCL2, and CXCL14, were validated in silico analysis. Finally, PPI network analysis using enriched data showed IL1B, CCL2, CCL7 and BMP7 were in the same hub node with high degrees.
We identified IL1B was significantly up-regulated in COPD small airway epithelial cells and propose IL1B as a novel player in airway inflammation in COPD.
KeywordsIL1B COPD Airway epithelial cells Inflammation
Interleukin 1 beta
Interleukin-1 receptor type 2
Chronic obstructive pulmonary disease
Chemokine (C-C motif) ligand 2
Chemokine (C-C motif) ligand 7
Chemokine (C-C motif) ligand 23
Hypoxia inducible factor-1 alpha
Differentially expressed genes
Aldehyde dehydrogenase 3 family, member A1
Dual oxidase 2
Matrix metalloproteinase 12
Aldo–keto reductase family 1, member B10
Cytochrome P450 family 1 subfamily B polypeptide 1
Gene set enrichment analysis
Kyoto Encyclopedia of Genes and Genomes
Weighted Gene Co-expression Network Analysis
We thank all members from department of central laboratory, the Fifth Affiliated Hospital of Guangzhou Medical University for their invaluable help.
ZYL, XKZ and JFL designed the study; ML (Min Liang), ML (Ming Li) and XMF performed data collection; GY and YXL analyzed the data; ZYL and GY wrote the manuscript. All authors read and approved the final manuscript.
This work was supported by the National Natural Science Foundation of China (Grant Number. 81400013), Science and Technology Planning Project of Guangdong Province, China (Grant Number. 2014A20212329) and Department of education of GuangDong Province, China (Grant Number. 2016KTSCX110).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
Ethical approval and consent to participate
In the current study, all analyses were based on publicly available data, and this article does not contain any studies with human participants and animals performed by any of the authors.
Consent for publication
- 10.Angelis N, Porpodis K, Zarogoulidis P, Spyratos D, Kioumis I, Papaiwannou A, et al. Airway inflammation in chronic obstructive pulmonary disease. J Thorac Dis. 2014;6(Suppl 1):S167–72.Google Scholar
- 17.Davies C, Rhodes JA, Barnes P, Donnelly L. Elevated CCL2 responses in COPD and attenuation by selective chemokine receptor antagonists. Eur Respir J. 2015;46(suppl 59):PA3900.Google Scholar
- 18.Abdel-Halim M, Darwish SS, ElHady AK, Hoppstadter J, Abadi AH, Hartmann RW, et al. Pharmacological inhibition of protein kinase C (PKC)zeta downregulates the expression of cytokines involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Eur J Pharm Sci Off J Eur Fed Pharm Sci. 2016;93:405–9.Google Scholar
- 19.Qin S, Huleihel L, Lucht L, Clarke A, Ries JW, Kessinger C, et al. Alterations of inflammatory chemokine and matrix metalloproteinase mRNA levels in BAL cells from HIV-infected COPD patients. Am J Resp Crit Care. 2015;191:A4716.Google Scholar
- 22.Mehta H, Nazzal K, Sadikot RT. Cigarette smoking and innate immunity. Inflamm Res Off J Eur Histamine Res Soc [et al]. 2008;57:497–503.Google Scholar
- 23.Vogelmeier C, Koczulla R, Fehrenbach H, Bals R. Pathogenesis of chronic obstructive pulmonary disease. Der Internist. 2006;47(6):885–6 (888–90, 892–4).Google Scholar
- 28.Meihua G, Jian W, Nanshan Z. [esearch progress of the role of oxidative stress in the pathogenesis of COPD. Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chin J Tuberc Respir Dis. 2015;38:222–4.Google Scholar
- 32.Barnes PJ. Inhaled corticosteroids in COPD: a controversy. Respir Int Rev Thorac Dis. 2010;80:89–95.Google Scholar